Biologic Roles of Novel Axonal Guidance Genes in Isolated GnRH Deficiency

描述(申请人提供)：人类的生殖是由下丘脑促性腺激素释放激素(GnRH)神经肽的脉动性分泌控制的，GnRH神经元网络。GnRH神经元发育或分泌/作用的失败导致一种罕见的人类遗传病，称为孤立性GnRH缺乏症(IGD)。Kallmann综合征(KS)代表了一种独特的IGD神经发育形式，其特征与嗅觉障碍有关。到目前为止，与KS相关的基因只有30%是已知的。两个轴突引导基因KAL1和NELF的突变是最早发现的KS相关基因。然而，直到最近，还没有类似的轴突引导基因与KS有关。三个新的轴突引导基因的遗传、分子和表型特征形成了这一提议的基础。5名符合Moebius综合征(一种复杂的神经发育综合征)诊断的无关患者最近被发现存在一个影响TUBB3基因的从头杂合错义突变(p.E410K)，该基因编码一种称为神经元微管蛋白同型3的轴突引导分子。PI现已确定所有这些患者都显示KS，提示TUBB3是一个新的KS基因。此外，另一种轴突导向分子SEMA3A的突变和神经脊迁移基因Sox10的突变最近也被认为是KS的原因。在特定的目标1中，PI将通过研究突变的发生率、它们的分子原因机制以及它们与其他IGD基因的遗传交互作用来评估这三个参与轴突引导的新的神经发育基因(TUBB3、SEMA3A和SOX10)在IGD发病机制中的作用。在具体目标#2中，这三个基因突变的患者的生殖和非生殖表型将被检测，以确定它们在GnRH神经元个体发育和其他器官系统中的生物学作用。KS被认为代表了人类的一种异常轴突引导障碍，这一提议将为这一假说提供确凿的证据。该研究所的长期目标是成为一名独立资助的临床研究人员，并开发一项研究人类生殖障碍的综合研究计划。为了实现他的职业目标，PI组建了一个非常有活力的指导团队来监督他拟议的研究。此外，他还确定了主要的培训目标，这些目标将通过实际研究经验、课程作业和教学学习来实现。这一严格的职业发展和研究培训计划将帮助他在现有研究优势的基础上，获得新的临床研究技能，并促进他向独立的过渡。

DESCRIPTION (provided by applicant): Human reproduction is controlled by the pulsatile secretion of the hypothalamic neuropeptide, Gonadotropin-releasing hormone (GnRH), from a network of GnRH neurons. Failure of GnRH neuronal development or its secretion/action results in a rare human genetic disease called isolated GnRH deficiency (IGD). Kallmann Syndrome (KS) represents a distinct neurodevelopmental form of IGD which is characteristically associated with anosmia. To-date, only ~30% of genes linked to KS are currently known. Mutations in two axonal guidance genes, KAL1 and NELF were the first KS-associated genes to be discovered. However, until recently, no similar axonal guidance genes have been implicated in KS. The genetic, molecular and phenotypic characterization of three novel axonal guidance genes forms the basis of this proposal. Five unrelated patients fitting the diagnosis of "Moebius syndrome", a complex neurodevelopmental syndrome, were recently found to harbor a de novo heterozygous missense mutation (p.E410K) affecting the TUBB3 gene, which encodes for an axonal guidance molecule called neuronal ¿-tubulin isotype 3. The PI has now identified that all these patients also display KS, suggesting TUBB3 as a novel KS gene. In addition, mutations in SEMA3A, another axonal guidance molecule and mutations in SOX10, a neural crest migratory gene, were also recently implicated as cause of KS. In Specific Aim #1, the PI will assess the role of these three novel neuro-developmental genes involved in axonal guidance (TUBB3, SEMA3A, and SOX10) in the pathogenesis of IGD by studying the prevalence of mutations, their molecular causal mechanisms and their genetic interactions with other IGD genes. In Specific Aim #2, the reproductive and non-reproductive phenotypes of patients harboring mutations in these three genes will be examined to define their biological role in GnRH neuronal ontogeny and in other organ systems. KS has been thought to represent an aberrant axonal guidance disorder in humans and this proposal will provide confirmatory evidence to this hypothesis. The long term goal of the PI is to become an independently funded clinical investigator and develop a comprehensive research program to study disorders of human reproduction. To achieve his career goals, the PI has assembled a highly dynamic mentoring team to oversee his proposed research. In addition, he has identified key training objectives that will be achieved through practical research experience, coursework and didactic learning. This rigorous career development and research training plan will help him to build on his existing research strengths, acquire new clinical investigatory skills and facilitate his transition to independence.